6-fluoro steroids and process



United States Patent fiice 2,838,537 Patented June 10, 1958 2,838,537-VG-FLUORO STEROIDS AND PROCESS George B. Spero, Kalamazoo Township,Kalamazoo 1 County, Barney J. Magerlein, Kalamazomand William 1?.Schneider and John A. Hogg,.Kalamazoo Township, Kalamazoo; County,Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporationof Michlgan NolDr'awing.

Application November 29, 1957 Serial No. 699,500 i Claims. c1. 260-39145This invention relates to 1-dehydro-6,21-difluoro-9ahalo 21desoxyhydrocortisone and 1 dehydro 6,21-difluoro-9a-halo-2l-desoxycortisone and is more particularly concernedwith 1-dehydro-6a,9u,2l-trifluoro-Zl-desoxyhydrocortisone (6a,9ot,2ltrifluoro 115,170; dihydroxy 1,4 pregnadiene 3,20 dione), 1 dehydro-6a,9ct,21 trifiuoro 4 21 desoxycortisone (6a,9a,21-

' trifluoro 17a hydroxy 1,4! pregnadiene 3,11,20-

v dihydroxy-l,4rpregnadiene-3,20-dione) has been found to exhibitapproximately ten to, fifteentimes' the anti-inflammatory activity ofhydrocortisone, and in addition has a favorable effect on bodyelectrolyte balance. The compounds of this invention are useful in the.treatment of inflammatory conditions of the skin, eyes and ears ofhuma'nsand of valuable domestic animals, as well as contact dermatitisand other allergic reactions. Administration of thenovel steroids, canbe in conventional dosage fgorms, su c h as pills, tablets, capsules,syrups or elixirs for oral use, or in liquid forms which, are adaptableto the natural and synthetic cortical steroid hormones forinjectableproducts. The novel compounds can also be administeredtopically in the form of ointments, creams, lotions and the like, withor without coacting antibiotics, germicides or other materials formingadvantageous cornbinations therewith. 1 I H r I The compounds of thisinvention can be prepared in accordance with the following reactions:

onion CHzOSOzR 0:0 0:0 -on |---OH X q j] a CHgF wherein R is an organicradical, particularly a hydrocarbon radical containing from one to tencarbon atoms, inclusive, such as methyl, ethyl, phenyl, tolyl, naphthyl,or the like, methyl being preferred, and wherein X is a halogen ofatomic Weight between seventeen and eighty, inclusive, i. e., fluorine,chlorine or bromine.

As indicated above and described in greater detail below, the reactionsembodied in the processes characterizing this invention are susceptibleof variation in the specific steps leading to the final products III andV, the precise sequence selected being determined by such factors aseconomics and convenience.

It is an object of the present invention to provide l-de hydro 6,21difluoro c halo 21 desoxyhydrocortisone (III) and1-dehydro-6,21-difluoro-9a-halo-21- dcsoxycortisone ('V) and moreparticularly to provide 1 dehydro 6a,9u,21 trifluoro 21desoxyhydrocortisone and 1 dehydro 6a,9a,21 trifluoro 21-desoxycortisone. A further object is to provide processes for theproduction of 1-dehyd.ro-6,21-difluoro-9ahalo 21 desoxyhydrocortisoneand l dehydro 6,21- difluoro-9a-halo-21-desoxycortisone, including the6m and 6,8 epimers thereof.

The process of the present invention comprises treating 6 fiuoro 9a halo11/3,17a,21 trihydroxy 1,4- pregnadiene 3,20 dione (1 dehydro 6 fluoro9ozhalohydrocortisone) (I) with an organic sulfonyl halide to obtain thecorresponding 21-ester (II), a 21-alkyl or aryl sulfonate of6-fluoro-9a.-halo-11,8,17a,21-trihydroxyl,4-pregnadiene-3,ZO-dione, andthereafter treating the thus produced 21-a1kyl or aryl sulfonate with afiuorinating agent to obtain the corresponding 6,21-difluoro-9a-halo113,17a dihydroxy 1,4 pregnadiene 3,20 dione (III). The 6,21-difluoroproduct above can be oxidized i 3 to give the corresponding6,21-difluoro-9a-halo-17u-hydroxy-l,4-pregnadiene-3,11,20-trione (V).Alternatively, the 6 fluoro 9a halo 11B,17u,21 trihydroxy 1,4-pregnadiene-3,20-dione 21-alkyl or aryl sulfonate can be reacted with aniodinating agent such as sodium iodide to produce the corresponding2l-iodo steroid (IV), which can be fluorinated to yield the 21-fiuorosteroid (III). Similarly, when the ll-keto analogue(1-dehydro-6-fluoro-9a-halocortisone) is utilized as the startingmaterial in the above series of reactions, 6,21-difiuoro-9u-halo- 17ozhydroxy 1,4 pregnadiene 3,11,20 trione (V) is produced directly withoutthe step of oxidation of the 1 1 fl-hydroxyl.

The starting steroids for the compounds and process of the presentinvention are l-dehydro-6-fiuoro-9a-halohydrocortisone andl-dehydro-6-fluoro-9rz-halocortisone and are prepared in accordance withthe procedures of Preparations 1 through 26 herein. The preferredcompounds containing the 17(20)-double bond have the cis configurationbecause they are convertible in higher yields in the oxidativehydroxylation step than are the trans isomers, although both areoperative.

In carrying out the process of this invention, l-dehydro-6-fiuoro-9u-halohydrocortisone is treated with an organic sulfonylhalide such as methanesulfonyl chloride, toluenesulfonyl chloride,toluenesulfonyl bromide, benzenesulfonyl chloride, naphthylsulfonylchloride, and the like, the methanesulfonic acid halides, especiallymethanesulfonyl chloride, being preferred. In the preferred embodimentof this invention, the starting steroid is usually reacted with thealkyl or aryl sulfonyl halide in solution in a solvent such as pyridine,benzene, toluene, or the like. Where such solvents as benzene andtoluene are employed, an amount of an amine base such as pyridine atleast equal to the molar amount of the sulfonyl halide should also bepresent to react with the halogen acid formed. Reaction of the alkyl oraryl sulfonyl halide is conducted preferably at temperatures betweenminus ten and plus sixty degrees centigrade, provided that at the lowertemperatures the solvent has not solidified. Thus, for pyridine,dioxane, toluene, or the like, temperatures in the range of zero to tendegrees centigrade can be used, while for benzene only temperaturesabove five degrees centigrade are suitable because of the relativelyhigh freezing point of benzene. The reaction time is usually betweenabout four and 24 hours, after which the product, 6 fluoro 9oz halol1/3,17m,2l trihydroxyl,4-pregnadiene-3,ZO-dione 2l-alkyl or arylsulfonate (II), is recovered in a conventional manner, such as, forexample, by evaporating the solvent until a dry residue is obtained orby diluting the reaction mixture with Water and precipitating theproduct with dilute hydrochloric acid.

The 6 fluoro 9a halo llfi,l7u,2l trihydroxyl,4-pregnadiene-3,20-dione2l-alkyl or aryl sulfonate can first be converted to the corresponding2l-iodo compound (IV) which is readily convertible to the 2l-fluorosteroid. The 21-iodo compound is prepared by reacting the said 21-alkylor aryl sulfonate with an iodinating agent, such as .alkali metaliodide, e. g., sodium, potassium or lithium iodide, in an oxygenatedhydrocarbon solution such as an alkanone solution, e. g., acetone. Amolar excess of the iodide (three to twenty moles of iodide per mole ofsteroid) is preferred for this reaction. The reaction mixture containingthe 21-alkyl or aryl sulfonate and the alkali metal iodide in solutionis heated to reflux for a. period of about three minutes to thirtyminutes. The thus jproduced 6 fiuoro 9oz halo 21 iodo 11,8,17udihydroxy-l,4-pregnadiene-3,ZO-dione can then be isolated by evaporatingthe solvent or by drowning out with water and filtering. For thesubsequent reaction, the 21-iodo steroid can be used either in purifiedform as a product of recrystallization from such organic solvents asacetone,

4 ethanol, and the like, or it can be employed directly as a crudeproduct in the next step of the synthesis.

The 2l-iodo steroid (IV), dissolved in a solvent such as acetonitrile,dimethylformamide or ethylene glycol, is treated with a metal fluoridesuch as silver fluoride, antimony fluoride, potassium fluoride, or thelike, acetonitrile and silver fluoride being preferred. The metalfluoride should be added in small quantities at intervals, and thereaction mixture should, be protected from light dur ing the reactionperiod, which usually ranges from about one-half to six hours. Thereaction mixture is then concentrated and the product extracted as inprevious purification steps to yield essentially pure6,21-difluoro-9a-halo- 1 1B,17u-dihydroxy-1,4-pregnadiene-3 ,20-dione.

Alternatively, the6-fiuoro-9a-halo-11B,17m,2l-trihydroxy-l,4-pregnadiene-3,ZO-dione21-alkyl or aryl sulfonate is reacted with a fluorinating agent such aspotassium fluoride, silver fluorideor antimony fluoride in an inertsolvent such as dimethylsulfoxide, acetonitrile, dilnethylformamide orethylene glycol solution, the preferred combination being potassiumfluoride in dimethylsulfoxide. The reaction is advantageously conductedunder continuous heating, and it proceeds generally for a period ofaboutsix to 24 hours, fifteen to twenty hours usually being sufiici ent.The reaction mixture is then diluted with water and extracted with anorganic solvent such as methylene chloride, chloroform, benzene, and thelike, and purified in a conventional manner, as, for example, bychromatography or recrystallization.

The foregoing reactions constituting either the principal. oralternative routes can likewise be conducted on the correspondingll-keto analogues.

The oxidation of6,2l-difiuoro-9a-halo-llB,17a-dihydroxy-l,4-pregnadiene-3,20-dione canbe carried out by a variety of methods, ,such as, for example, byoxidizing the said 6,2l-' difiuor'o steroid in acetic acid solution withchromium trioxide, using molar quantities or a slight excess, such asfrom ten'to thirty percent excess, or by oxidizing with a haloamide'or'imide ofan acid, such as N-bromoacetamide, N-chlorosuccinimide, 'orN-bromosuccinirnide dissolved in pyridine, dioxane, or other suit ablesolvents. At the conclusion of the desired oxidation reaction, theexcess oxidant is generally destroyed by addition of methyl alcohol,ethyl alcohol, and the like for the chromic acid oxidant or a bisulfitefor N-brornoacetamide, N-bromosuccinimide and other N-halo acyl amidesand irnides. Thereafter, the resulting 6,2l-divfluoro 9a halo 171:hydroxy 1,4 pregnadiene 3, 11,20-trione is recovered by conventionalmeans, such as by extraction with watenimmiscible solvents, 'e. g.,methylene chloride, ether, benzene, toluene or the like, or bychromatography.

As hereinbefore indicated, the processes for the preparation oftheproducts of the present invention are susceptible of variation. Asshown in Preparations 13 through 16 1-dehydro-6-fiuorohydrocortisoneacetate is converted to 'l-dehydro-6-fluoro-9a-halohydrocortisoneacetate by introduction of the 9a -halogen into the molecule. The1-dehydro-6-fluoro-9a-halohydrocortisonc is then fluorinated at carbonatom 21 as shown in the examples. Alternatively, if desired,fiuoroination at carbon atoms 21 can be done first and this can then befollowed by halogenation at carbon atom 9. Thus, treatingl-dehydro-6-fluorohydrocortisone with an organic sulfonyl halide isproductive of the 21-sulfonate which on treatment with a fluorinatingagent such as potassium fluoride or silver fluoride gives6,2l-difluoro-11,8,17a-dihydroxy- 1,4-pregnadiene-3,20-dione. The6,2l-difluoro compound can be dehydrated with N-bromoacetamide andanhydrous sulfur dioxide in pyridine solution by permitting the reactionto continue until a negative acidified potassium iodide-starch testofthe reaction mixture is obtained. Dilution with cold water results inthe precipitation of 6,2l-difluoro-17u-hydroxy-1,4,9 1 1)-pregnatriene-3,20-dione, which can be purified by recrystallizationfrom aceby chromatography and can be further purified byrecrystallization from Skellysolve B hexanes-acetone. Reaction of thesaid 9,11-oxido compound in methylene chloride solution with aqueoushydrogen fluoride or liquid hydrogen fluoride in the presence oftetrahydroturan is productive of6,9a,21-trifluoro-11B,17a-dihydroxy-1,4- pregnadiene-3,20-dione.Substitution of aqueous hydrogen chloride for the hydrogen fluorideabove yields 6,21- difluoro 90 chloro-l15,17a-dihydroXy-1,4-pregnadiene-3,20-dione. product can be oxidized, for example, with N-bromoacetamidein pyridine solution, or with chromic acid to give6,9a,21-t1iflu0ro-17ot-hydroxy-3,11,20-trione or the corresponding90t-Cl'1l01'0 compound. p

In the foregoing processes, it should be understood that thecorresponding 6fi-halo epimer can be utilized at any stage and the6a-epirner obtained at appropriate intermediate stages by treatment ofthe 6(3-compound, at

temperatures of zero degrees centigrade or slightly lower, in an organicsolvent such as chloroform and in the presence of alcohol, with ananhydrous mineral acid, such as hydrochloric acid. The reducedtemperatures should be maintained throughout the period of addition ofthe acid. The reaction mixture can then be washed with successiveportions of dilute alkali and water and evaporated under reducedpressure to obtain the 6ot-epimer in high yield.

The following preparations and examples are illustrative of the processand products of the present invention but are not to be construed aslimiting.

PREPARATION 1 3-ethylene ketal of methyl 3,1I-dikQm-Smfia-Oxido 1 7(20)-[cis] -pregnen-21 -oate To a solution of five grams of the 3-ethyleneglycol ketal of methyl 3,11-dilceto-4,17(20)-[cis]-pregnadien-21- oate,prepared in the manner described in U. S. Patent 2,707,184, in 100milliliters of chloroform was added a chilled solution of 1.9 grams ofperbenzoic acid dissolved in 315 milliliters of chloroform. The solutionwas maintained at about four degrees centrigrade for 24 hours, and thenat room temperature for 72 hours. The solution was washed with a fivepercent aqueous solution of sodium bicarbonate and then with water. Thechloroform layer was separated, dried and the solvent distilled to givea residue of 5.3 grams of solid. Crystallization of this solid frommethanol gave 2.24 grams of product melting at 180 to 195 degreesCentigrade, and after two crystallizations from methanol there wasobtained pure 3-ethylene ketal of methyl 3,11-diketo-5a,6ct-oxido-17(20)-[cisl-pregnen-21-oate melting at 206 to 209 degrees centigradeand having an [al of plus 37 degrees (CHCl and the following analysis:

Calculated for 11 0 C, 69.20; H, 7.75. Found: C, 69.59; H, 7.81.

PREPARATION 2 Methyl 3,11-diket0-5a,6fl-dihydroxy-17(20) -all0pregnen-To a solution of 1.73 grams of 3-ethylene ketal of methyl 3 ,1l-dikclO-u,6oc-OXidO-17 [cis] -pregnen-21- pate in sixteen millilitersof methylene chloride was added If desired, either the 9ot-fluoro orchloro' six milliliters of 48 percent hydrofluoric acid. The heterogeneous mixture was stirred for two hours, made slightly basic with 300milliliters of five percent sodium bicarbonate solution, and extractedwith methylene chloride. The extract was washed, dried, and evaporatedto dryness to give 1.62 grams of crude solid. Purification bychromatography over synthetic magnesium silicate gave two fractions: A,481 milligrams eluted with methylene chlorideplus five percent acetone,and B, 921 milligrams eluted with methylene chloride plus ten and twentypercent acetone. Crystallization of fraction A from acetone- SkellysolveB hexanes gave 390 milligrams of methyl 3 ,1 ldiketo-5a-hydroxy-6fl-fiuoro- 17 (20) -allopregnen-21- oate, meltingpoint 254 to 260 degrees Centigrade. The analytical sample melted at 260to 263 degrees centigrade.

A.nalysis.Calculated for C H O F: F, 4.84. Found: F, 4.47.

PREPARATION 3 M ethyl 3,11 diketo Sa-hydroxy-dB-fluoro-Z 7(20)-all0-pregnen-ZI-oate 3-ethylene ketal A mixture of 1.9 grams of methyl3,11-diketo-5a-hydroxy 6B fluoro17(20)-allopregnen-21-oate, 59milligrams of p-toluenesulfonic acid monohydrate and 31 milliliters ofdistilled ethylene glycol was added to 800 milliliters of benzene. Themixture was stirred and refluxed for two hours, with the condensatepassing through a Water trap to remove the water. After reflux themixture was cooled, washed with water and evaporated to dryness to givea crude solid which on recrystallization from acetone-Skellysolve Bhexanes gave 1.96 grams of methyl 3,11diketo-5a-hydroxy-6j8-fluoro-l7(20) -allopregnen-2 1 PREPARATION 4 50a,] 1 {1,2 I -trihydr0xy-6B-flu0r0-1 7(20) -allopregnen-3-- one3-ethylene ketal To a solution of 1.96 grams of methyl 3,1l-diketc-5ahydroxy-6/3-fluoro- 17 20 -:allopregnen-2 l-oate S-ethylene ketal in 850milliliters of anhydrous ether was added 3.7 grams of lithium aluminumhydride. The mixture was stirred for a period of one hour, and 200milliliters of water was added slowly, the ether phase separating. Theaqueous phase was extracted with ethyl acetate and the extracts added tothe ether phase. The combined etherethyl acetate solution was washedwith water, dried and evaporated to dryness under reduced pressure. Thecrude solid residue was crystallized from acetone-Skellysolve B hexanesto give 1.30 grams of 5a,11B,21-trihydroxy 6,3 fiuorol7(20)-allopregnen-3-one B-ethylene ketal, melting point 197 to 205degrees centigrade. An additional 226 milligrams was obtained from themother liquor, melting point 175 to 185 degrees centigrade.

PREPARATION 5 5a,11B-dihydr0xy-6 3-flu0r0-21-acetoxy-17(20)-all0-pregnen-S-one 3-ethylene ketal The acetate was prepared by allowing 0.87gram of 5a,l1;3,21-trihydr0xy 65 fiuoro-l7(20)sallopregnen-3- one3-ethylene ketal to stand overnight in ten milliliters of aceticanhydride and ten milliliters of pyridine. The solution was then pouredinto ice water to give 0.92 gram of5a,1lB-dihydroxy-6B-fluoro-2l-acetoxy-17(20)- allopregnen-B-one3-ethylene ketal, melting point to degrees centigrade, which onrecrystallization from acetone-Skellysolve B hexanes gave 0.77 gram,melting point 149 to 153 degrees centigrade.

Similarly, other 2l-organic carboxylic esters of5a,115,2l-trihydroxy-GB-fluoro 17(20) allopregnen-3- a'solvent such asbenzene, toluene, pyridine, or the like.

' PREPARATION 6 5 c, 1 1 [3,1 7 a-trihydr0xy-6 fi-fluoro-ZI-acetoxyallopregnane- 3,20-di0ne 3-ethylene ketal To a solution of 0.77gram of 5a,11B-dihydroxy-6[ifiuoro-Zl-acetoxy 17(20) allopregnen-S-one3ethylene ketal in 35 milliliters of tertiary butyl alcohol was addedone milliliter of pyridine, 1.9 milliliters of N-methylmorpholine oxideperoxide solution, and 13.1 milliligrams of osmium tetroxide (9.1milliliters of tertiary butyl alcohol solution containing 1.44milligrams of osmium tetroxide per milliliter). The solution was stirredfor a period of 2.5 hours and fifteen milliliters of five percent sodiumhydrosulfite was added. Stirring was continued for an additional tenminutes, at which time 0.7 gram of finely ground synthetic magnesiumsilicate was mixed into the solution for a period of twenty minutes andthen removed by filtration. The filtrate was evaporated to dryness underreduced pressure at a temperature of less than fifty de greescentigrade. The residue was dissolved in methylene chloride, washed withWater, dried and evaporated to dryness. This residue was crystallizedfrom acetone- Skellysolve B hexanes to give 0.47 gram of5a,11,8,17atrihydroxy-6fl-fiuoro 21-acetoxyallopregnane-3,ZO-dione3-ethylene ketal, melting point 220 to 228 degrees centigrade.

PREPARATION 7 A solution of 0.47 gram of 5a,11;3,17x-trihydroxy-6B-fluoro-2l-acetoxyallopregnane-3,20-dione 3-ethylene ketal in 35milliliters of acetone and four milliliters of 1 N sulfuric acidsolution was gently boiled on a steam bath for ten minutes, cooled andneutralized with dilute sodium bicarbonate solution. Addition of waterfollowed by cooling gave 0.33 gram of 5e,11 9,17a-trihydroxy-6/3-fluoro21-acetoxyallopregnane-3,20dione, melting point 230 to 24-0degrees Centigrade.

PREPARATION 8 6 dfluorm] 1 5,1 7a-dihydroxy-21-acetoxy-4-pregnene-3,20-di one (6 fi-fluorohydrocortisone acetate) A solution of 100 milligramsof 5 a,11, 3,l7o-trihydroxy-6fi-fiuoro-2l-acetoxyallopregnane-3,ZO-dione in 4.9 milliliters ofacetic acid and 0.1 milliliter of water was refluxed for a period of onehour, cooled, diluted with fifty milliliters of water and evaporated todryness under reduced pressure. The residue was chromatographed oversynthetic magnesium silicate to give one fraction (77 milligrams) elutedwith methylene chloride plus ten percent acetone. Crystallization fromacetone-Skellysolve B hexanes gave 38 milligrams of6[Jfitl01'O-11B,l7adihydroxy-Z l -acetoxy-4-pregnene-3,20-dione(6t3-fiuorohydrocortisone acetate), melting point 210 to 218 degreescentigrade. Infrared data and ultraviolet data were in agreement withthe structure.

PREPARATION 9 6 fi-flu0r0-1 1 19,17ix-dihydroxy-21-acet0xy-4-pregnene-3,20- dione 6 wfluorohydrocortisoneacetate) centigrade.

8 droxy-21-acetoxy-4-pregnene-3,20-dione in twelve milliliters ofchloroform and 0.1 milliliter of absolute alcohol was cooled to minusten degrees centigrade in an ice-salt bath. A stream of anhydroushydrochloric acid was gently bubbled through the solution for 2.5 hours,during which period the temperature was maintained between minus fiveand minus fifteen degrees centigrade. The solution was then diluted with25 milliliters of chloroform, washed with dilute aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure at sixty degreesCrystallization of the residue from acetone- Skellysolve B hexanes gave42 milligrams of the isomerized product,6a-fiuoro-11,3,17a-dihydroxy-21-acetoxy-4- preguene-3,20-dione, whichmelted at 203 to 210 degrees Centigrade.

PREPARATION 10 A solution of 1.1 grams of6u-fluoro-11fi,17a-dihydroxy-Z1-acetoxy-4-pregnene-3,20-dione, one gramof potassium bicarbonate, milliliters of methanol and fifteenmilliliters of water were mixed together and purged with nitrogen toremove dissolved oxygen while stirring at 25 degrees centigrade for fourhours. The solution was then neutralized by addition of acetic acid anddistilled under vacuum to remove the methanol. The residue was extractedwith 100 milliliters of methylene dichloride, and the extract was driedover sodium sulfate and passed through a column containing eighty gramsof synthetic magnesium silicate. The fraction eluted with Skellysolve Bhexanes plus twenty and thirty percent acetone weighed 770 milligrams,representing a yield of 77.5 percent. Recrystallization of a portion ofthis crude product from ethyl acetate-Skellysolve B hexanes gavecrystals melting at 192 to 195 degrees centigrade.

PREPARATION 1 1 1-dehydr0-6u-fluorohydrocortisone Five 100-milliliterportions of a medium, in 250-milliliter Erlenmeyer flasks, containingone percent glucose, two percent corn steep liquor (sixty percentsolids) and tap water, were adjusted to a pH of 4.9. This medium wassterilized for 45 minutes at fifteen pounds per square inch pressure andinoculated with a one to two day growth of Septomyxa afiinis A. T. C. C.6737. The Erlenmeyer flask was shaken at room temperature (about 26 to28 degrees centigrade) for a period of three days. At the end of thisperiod this SOD-milliliter volume was used as an inoculum for ten litersof the same glucose-corn steep liquor medium which in addition containedten milliliters of an antifoam compound (a mixture of lard oil andoctadecanol). The fermenter was placed into the water-bath, adjusted to28 degrees centigrade and the contents stirred (300 R. P. M.) andaerated (0.3 liter air to five liters of beer). After 24 hours ofincubation, when a good growth had been developed, five grams of6e-fluorohydrocortisone acetate plus one-half gram of3-ketobisnor-4-cholen-22-al, dissolved in 25 milliliters ofdimethylformamide was added and the incubation carried out at the sametemperature (28 degrees centigrade) and aeration for a period of 72hours (final pH 8.3). The rnycelium was filtered ofi and washed withwater. The wash water was combined with the filtrate and the whole wasextracted with three two-liter portions of a mixture ofmethylenechloride-ethyl acetate (3:1). Removal of the solvent byevaporation gave 5.25 grams of crude solid which was triturated twicewith four milliliters of methylene chloride to give 2.4 grams ofl-dehydro-6u-fluorohydrocortisone of melting point 198 to 203 degreescentigrade. The analytical sample, recrystallized from acetone, meltedat 202 to 204 degrees centigrade. Analysis gave [al plus 73 degrees(dioxane) and the following:

Analysis.-Calculated for C21H27O5FZ C, 66.65; H, 7.10; F, 5.02. Found:C, 66.68; H, 7.19; F, 5.49.

Substitution of the 6p-epimer'for the starting material above isproductive of 1-dehydro-6,8-fluorohydrocortisone. The GB-epimer can beconverted to the 6a-epimer following the procedureof Preparation 9PREPARATION 12 6a-flu0r0-1 118,1 7a-dihydr0xy-21 -ace foxy-1,4-pregnadiene 3,20-dione (1-dehydro-6a-fluorohydrocortisorze acetate) Asolution of two grams of 1-dehydro-6a-fluorohydrocortisone in tenmilliliters of pyridine and ten milliliters of acetic anhydride wasallowed to stand at room temperature for seventeen hours, and was thenpoured into a mixture of ice and water; The resulting crystallineproduct was isolated by filtration, washed with water and dried. Theyield of 1-dehydro-6a-fluorohydrocortisone acetate was 1.32 grams ofmelting point 232 to 237 degrees centigrade. The analytical samplemelted at 238 to 242 degrees centigrade. Analysis gave [:11 plus 102degrees (acetone) and the following:

Analysis.Calculated for C- H O F: C, 65.70; H, 6.95; F, 4.52. Found: C,65.58; H, 7.16; F, 4.39.

PREPARATION 13 To a solution of 1.05 grams of1-dehydro-6a-fluorohydrocortisone acetate in ten milliliters of pyridine"was added 0.517 gram of N-bromoacetamide. The mixture was allowed tostand under nitrogen for fifteen minutes, at which time it was cooled tofive degrees centigrade. While stirring, sulfur dioxide waspassed overthe surface until the solution gave no color change with acidifiedstarch-iodide paper. The temperature of the reaction mixture Was notallowed to go above twenty degrees centigrade during the sulfur dioxideaddition. The mixture was then poured into 100 milliliters of ice-water,resulting in precipitation of 977 milligrams of 6a-fluoro-17u-hydroxy-21 acetoxy 1,4,9(11) pregnatriene 3,20- dione, melting point186 to 196 degrees centigrade (with decomposition). The analyticalsample melted at 213 to 216 degrees centigrade (with decomposition).Analysis gave [111 plus 34 degrees (acetone) and the following:

Analysis.Ca1culated for C23H2705F: C, 68.64; H, 6.76; F, 4.72. Found: C,68.85; H, 6.86; F, 4.72.

PREPARATION 14 sot-fluom-yu-bmmo-zlaua dzh dmx -zi acetoxy 1,4pregnadiene-3,20-dine (1-dehydr0=6a-fluoro-9a-bromohydrocortisoneacetate) To a solutionof 1.27 grams of 6a-fluoro-l7a-hydroxy-21acetoxy-1,4,9(11)-pregnatriene-3,20-dione in 19.5 milliliters ofmethylene chloride was added 38 milliliters of tertiary butyl alcohol, asolution of three milliliters of 72 percent perchloric acid in 22.5milliliters of water, anda solution of 0.55 gram of N-bromoacetamide in9.6 milliliters of tertiary butyl alcohol. After stirring for fifteenminutes, a solution of 0.55 gram of sodium *sulfite in thirtymilliliters of water was added and the mixture concentrated underreduced pressure at sixty degrees centigrade until crystallizationoccurred. After cooling in an ice bath, 100 milliliters of water wasadded with stirring. On filtering the crystalline product, followed bywashing with water and drying, a yield of 1.59 grams of essentially pure6a-flu'oro-9a-bromo-1113,17a-dihydroxy- 21 acetoxy-1,4pregnadiene-3,20-dione, melting point 188 to 191 degrees centigrade(with decomposition) was obtained. The product was used in thesucceeding-example Without further purification.

Substitution of N-iodosuccinimide forthe N-bromo- '10 acetamide intheforegoing reaction is productive of the corresponding 9a-iodo product.

PREPARATION 15 A mixture of 1.749 grams of 6a-fluoro-9a-bromo-llp,17a-dihydroxy-21-acetoxy-l,4-pregnadiene-3,20-dione(ldehydro-6a-fiuoro-9a-bromohydrocortisone acetate), 1.749 grams ofpotassium acetate, and fifty milliliters of acetone was stirred andheated at reflux temperature for eighteen hours. The reaction mixturewas then concentrated to about one-half the original volume, cooled andpoured into BOO-milliliters of water to give 1.303 grams of 60afiuoro-93,11B oxido 17or-hydroxy-21-acetoxy-1,4-prega diene-3,20-dione, meltingpoint 234 to 238 degrees centigrade (with decomposition). The analyticalsample, recrystallized from acetone, melted at 257 to 260 degreescentigrade. Analysis gave [05],; plus seventy degrees (acetone) and thefollowing:

Analysis.Calculated for C H O F: C, 66.01; H, 6.50; F, 4.54. Found: C,65.73; H, 6.58; F, 3.87.

PREPARATION 16 To 5.2 grams of liquid hydrogen fluoride cooled inDry-Ice bath, was added, portion-wise, a slurry of 2.276 grams of6u-fiuoro-9B,11B-oxido-17a-hydroxy-2l-acetoxy-1,4-pregnadiene-3,20-dione in nine grams of tetrahydrofuran (distilledover NaOH) and 28 milliliters of methylene chloride which had similarlybeen cooled in a Dry- Ice bath. The steroid dissolvedcompletely. Afterstanding at zero to five degrees centigrade forseventeen hours, thereaction mixture was poured slowly into a stirred mixture of 500milliliters of water and 25 grams of sodium bicarbonate. The mixture wasstirred for a few minutes, and the product was extracted with three-milliliter portions of methylene chloride. The methylene chloridesolution was washed with water, dried, and chromatographed oversynthetic magnesium silicate. The fraction eluted from the column withfifteen and twenty percent acetone in Skellysolve B hexanes wasrecrystallized from ethyl acetate-Skellysolve B hexanes to give 1.342grams of product, melting point 238 to 242 degrees centigrade. Theanalytical sample melted at 239 to 242 degrees centigrade. Analysis gave[ul plus 91 degrees (acetone) and the following:

Analysis-Calculated for C H O F C, 63.00; H, 6.44; F, 8.67. Found: C,63.23; H, 6.82; F, 8.14.

Substitution of aqueous hydrogen chloride for the hydrogen fluorideabove is productive of the corresponding 9a-chloro product.

PREPARATION 17 605911, difluoro-l 15,1 711,2]-trihydroxy-1,4-pregnadiene-3, ZO-dione(1-dehydr0-6a,9u-difluorohydrocortisone) Nitrogen was bubbled through asolution of 1.4 grams of 60:,9nL-diflll0l'O-1 1,8,l7a-dihydroxy-21acetoxy-1,4-pregnadiene-3,20-dione(1-dehydro-6a,9u-difluorohydrocortisone acetate) in milliliters ofmethanol for fifteen minutes. To this was added a solution of 1.4 gramsof potassium bicarbonate in 17.5 milliliters of water likewise treatedwith nitrogen. After stirring under nitrogen for five hours, the basewas neutralized by the addition of 1.5 milliliters of acetic acid inforty milliliters of water. The mixture was then concentrated underreduced pressure at 55 degrees centigrade until crystallization started.The slurry was then cooled in an ice bath, diluted with 100 millilitersof water, and filtered to give 0.892 gram of6a,9a-difiuoro-1113,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione(1-dehydro-6a,9a difluorohydrocortisone), melting point 232 to 242degrees centigrade (with decomposition). The analytical sample melted at250 to 257 degrees centigrade (with decomposition).

Analysis gave [ul plus 84 degrees (acetone) and the following:

Analysis.Calculated for C H O F C, 63.62; H,

6.61; F, 9.59. Found: C, 62.76; H, 7.10; F, 9.41.

PREPARATION 18 6oz fluoro 9a-chloro-11/3J7a,21-trihydr0xy-I,4-pregnadiene-3,20-di0ne(1dehydr0-6aaoro-9a-chlorohydrocortisone) Following the procedure ofPreparation 17, substitution of1-dehydro-6a-fluoro-9a-chlorohydrocortisone acetate from Preparation 16for 1-dehydro-6a,9a-difluorohydrocortisone acetate is productive of1-dehydro-6afluoro-9u-chlorohydrocortisone.

v PREPARATION 19 6a fluoro9m-bromo-11,3,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione(1-dehydro-6a-fluoro-9a-brom hydrocortisone) Following the procedure ofPreparation 17, substitution of1-dehydro-6a-fluoro-9a-bromohydrocortisone acetate from'Preparation 14for l-dehydro-6a,9a-difluorohydrocortisone acetate is productive ofl-dehydro-fia-fluoro- 9m-bromohydrocortisone.

Alternatively, the removal of the acetate from1-dehydro-6a-fluoro-9a-bromohydrocortisone acetate toproduce';1-dehydro-fia-fluoro-9a-bromohydrocortisone is accomplishedunder acid conditions, such as, for example, methanolic hydrochloricacid.

PREPARATION 20 6m,9a-difluoro-17a-hydroxy 21 acetoxy 1,4pregnadiene-SJLZO-trione (I-dehydro 60;,90: difluorocortisone acetate) Asolution was prepared containing 0.5 gram of 6u,9adifluoro 11,6,17adihydroxy 21 acetoxy-1,4-pregnadiene-3,20-dione(1-dehydro-6a,9a-difluorohydrocortisone acetate), 0.15 gram'of chromiumtrioxide, ten milliliters of glacial acetic acid and one-half milliliterof water.

'This mixture was stirred and maintained at room tem- Preparation 14 isproductive of 1-dehydro 6a-fluoro-9abromocortisone acetate.

PREPARATION 23 6 ,9a-difluoro-1 71,21 -dihydroxy1,4-pregnadiene-3,11,20-trione (1dehydro-6a,9a-difluorocortisone) Following the procedure ofPreparation 17 but substituting 1-dehydro-6a,9a-difluorocortisoneacetate as the dehydro 63,90: difluorohydrocortisone, 1'- dehydro 613-12 starting material therein is productive'of 1dehydro-6a,9adifluorocortisone.

PREPARATION 24 6a-fluor0-9a-chloro-17oa,21 -dihydroxy 1,4 pregnadiene-3,11,20-tri0ne 1 -dehydro-6a-fluoro-9a-ch lorocortisone) Following theprocedure of Preparation 17 but substituting 1dehydro-6arfluoro-9a-chlorocortisone acetate of Preparation 21 as thestarting material therein is productive of1-dehydro-6a-fluoro-9ix-chlorocortisone.

PREPARATION 25 6a-fluoro-9u-bromo-17a,21-dihydroxy 1,4.- pregnadiene-3,1 1,20-trione (1-dehydro-6a-fluoro-9u-bromocortisone) Following theprocedure of Preparation 17 but substituting1-dehydro-6a-fluoro-9u-bromocortisone acetate of Preparation 22 as thestarting material therein is productive of1-dehydro-6a-fluoro-9a-bromocortisone.

PREPARATION 26 6fl-epimers Substituting 6p-fluorohydrocortisone acetatefor starting material in Preparation 11 and retaining the 65configuration in subsequent steps by careful maintenance of near neutralreaction condition, 6,8-epimers, such as 1-fluoro-9a-chlorohydrocortisone, 1dBhYdI'O-Gfi-flllOI'O-9abromohydrocortisone,1-dehydro-65,9a-difluorocortisone,1-dehydro-6;3-fluoro-9a-chlorocortisone and1-dehydro-6afluoro-9a-bromocortisone, are produced. The thus obtained 68-epimers yield the 6a-epimers by treatment with acid according to theprocedure of Preparation 9.

EXAMPLE 1 6a,9a difluOro-IJ 3,17a,21-trihydroxy 1,4 pregnadiene-3,20-dione ZJ-methanesulfonate To a solution of 0.925 gram of6a,9u-difluoro-11fl,17m,- 2l-trihydroxy-l,4-pregnadiene-3,20-dione 'inten milliliters of pyridine previously cooled to zero to five degreescentigrade was added 0.9 milliliter of methanesulfonyl chloride. Thereaction mixture was stirred at zero to five degrees centigrade forseventeen hours, and was then poured into milliliters of cold fivepercent hydrochloric acid to precipitate the solid mesylate. Theproduct, after filtration, weighed 0.832 gram, and had a meltingpoint of157 degrees centigrade (with decomposition). This was used in the nextstep without further purification.

EXAMPLE 2 3,20-dione (1 dehydro6a,9a,2I-trifluoro-2I-desoxyhydrocortisone) A mixture of 0.5 gram of6a,9a-difluoro-11fl,l7a,21- trihydroxy 1,4 pregnadiene-3,20-dione21-methanesulfonate and 0.37 gram of potassium fluoride in tenmilliliters of dimethylsulfoxide was stirred and heated on a steam bathfor seventeen hours. The reaction mixture was then cooled, poured intomilliliters of water, and extracted with four 100-milliliter fractionsof ethyl acetate. After drying over sodium sulfate, the ethyl acetatesolution was evaporated to dryness and the residue (452 milligrams) waspurified by chromatography over a column of synthetic magnesium silicateand crystallization from acetone-Skellysolve B hexanes to give 63milligrams of6a,9a,21-trifluoro-11fi,17a-dihydroxy-1,4-pregnadiene-3,20-dione ofmelting point 267 to 272 degrees centigrade (with decomposition). Theanalytical sample recrystallized from ethyl acetate, melted at 273 to277 degrees centigrade.

Analysis-Calculated for C H O F EXAMPLE 3 To a solution of 0.5 gram of6a.,9oi-difluoro-115,17u,21- trihydroxy-1,4-pregnadiene 3,20 dione21-methanesulfonate in 65 milliliters of acetone was added a solution of0.65 gram of sodium iodide in seven milliliters of acetone. '1 hemixture was allowed to reflux on the steam bath for about ten minutesand was then concentrated to dryness under reduced pressure. Theresulting 21- iodide was dissolved in 55 milliliters of acetonitrile atfifty to sixty degrees centigrade, in the dark, and was treated with 0.4milliliter of fifty percent aqueous solution of silver fluoride.Addition of silver fluoride was in three equal portions at one-half hourintervals. After maintaining at this temperature for a total of one andone-half hours, the temperature was lowered to forty to fifty degreescentigrade for an additional two and onehalf hours. The solvent was thenremoved under reduced pressure at fifty degrees centigrade and the blackresidue was digested with three fifty-milliliter portions of acetone.The product, contained in the acetone solution, was purified bychromatography over a column of synthetic magnesium silicate andcrystallized. from acetone-Skellysolve E hexanes to give crystallinel-dehydro-6a,9u,2l-trifluoro- 21-desoxyhydrocortisone.

EXAMPLE 4 6a,21 difluoro 9a chloro 115,170: dihydroxy 1,4-pregnadiene-iZO-dione (I dehydr 6m2I-difluvro-Qach Zora-21-des0xyhydr0cortisone) Following the procedures of Examples 1 through 3but substituting 1-dehydro-6u-fluoro-9a-chlorohydrocortisone ofPreparation 18 as starting material therein is productive of 1 dehydro611,21 difluoro-9a-chloro-2l-desoxyhydrocortisone.

EXAMPLE 5 60:21 difluoro 9a bromo -.115,17a dihydroxy 1,4-pregnadiene-3320-di0ne (1dehydro-60:21-diflzwro-9abromo-21-des0xyhydr0c0rtisone) Following theprocedures of Examples 1 through 3, but substituting1-dehydro-6a-fiuoro-9a-bromohydrocortisone of Preparation 19 as startingmaterial is productive of 1 dehydro 611,21difluoro-9a-bromo-2l-desoxyhydrocortisone.

EXAMPLE 6 6a,9a,21 trifluoro 170a hydroxy 1,4-pregadiene- 3,1 1,20-trione (1-dehydr0-6a,9a,21-triflu0r0 21-des0xycortisone) A solution isprepared containing 0.5 gram of 6a,9a,21- trifluoro 115,17ot dihyroxy1,4 pregnadiene 3,20- dione, 0.15 gram of chromium trioxide, tenmilliliters of glacial acetic acid and one-half milliliter of water.This mixture is stirred and maintained at room temperature for eighthours. Thereafter, the excess oxidant is destroyed by addition ofmethanol and the mixture is poured into fifty milliliters of ice water.The resulting precipitate is collected on a filter and recrystallizedfrom ethyl acetate to give 6a,9a,21-trifluoro-17a-hydroxy-1,4-pregnadiene-3,1 1,20-trione.

EXAMPLE 7 6a,9oc,21 trifluoro 17a hydroxy 1,4-pregadiene- 3,11,20-tri0ne(1-dehydr0-6a,9a,21-diflu0r0-21-des0xycortisone) In the same mannershown in Examples 1 and 2, treating6a,9'a-difluoro-17a,2l-dihydroxy-1,4-pregnadiene- 3,11,20-trione withmethanesulfonyl chloride in pyridine solution yields6a,9a-difluoro-17a,21-dihydroxy-1,4-pregnadiene 3,11,20 trioneZI-methanesulfonate. Heating Following the procedure of Example 6,oxidation of l dehydro 60,21 .difluoro -9a chloro21-desoxyhydrocortisone of Example 4 is productive of l-dehydro-6a,2l-difluoro-9a-chlor0-2l-desoxycortisone.

Alternatively, 1 dehydro 6u,21-difiuoro-9a-chlor0-21- desoxycortisone isprepared by following the procedures of Examples 1 and 2 andsubstituting l-dehydro-6afiuoro-9a-chlorocortisone of Preparation 24 asstarting material therein.

EXAMPLE 9 60:,21 difluoro 9oz bromo 17a hydroxy 1,4 pregnadiene 3,11,20trione (1dehydro-6:121-a'ifluoro-9zxbromo-21 -des0xycortis0ne) Followingthe procedure of Example 6, oxidation of 1 dehydro 60:,21 difiuoro 9abromo 21 desoxyhydrocortisone of Example 5 is productiveof l-dehydro-60:,2l-difluoro-9a-bromo-2l-desoxycortisone.

Alternatively, 1 dehydro-6o 21-difiuoro-9a-bromo-21- desoxycortisone isprepared by following the procedures of Examples 1 and 2 andsubstituting 1-dehydro-6ot-fiuoro- 9a-bromocortisone of Preparation 25as starting material therein.

EXAMPLE 10 6 5-epimers Substituting1-dehydro-65,9a-difiuorohydrocortisone or other 1 dehydro 65 fluoro9a-halohydrocortisones or -cortisones for the starting material inExample 1 and retaining the 65 configuration in subsequent steps bycareful maintenance of near neutral reaction conditions, 65-epimers,such as 65,9oa,21-trifluoro-115,17u-dihydroxy- 1,4 pregnadiene3,20-dione, 65,21 difiuoro Qua-chloro- 115,170: dihydroxy 1,4pregnadiene-3,20-dione, 65,21-

difluoro 9o: bromo 115,170 dihydroxy 1,4-pregnadiene-3,20-dione,65,21-difluoro17ot-hydroxy-1,4-pregnadiene 3,11,20 trione, 65,21difluoro 9ot-Chl0lO-l7ahydroxy 1,4 pregnadiene-3,11,20-trione,65,21-difiuoroc bromo 17a hydroxy 1,4-pregnadiene 3,11,20- trione, areproduced. The thus obtained 65-epimers yield the correspondingGa-epimers by treatment with acid according to the procedure ofPreparation 9.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art. The invention is therefore to be limited only by the scope ofthe appended claims.

We claim:

1. A compound selected from the group consisting of 1' dehydro 6,21difiuoro 9a halo 21 desoxyhydrocortisone and 1 dehydro 6,21 diiluoro9ahalo-21-desoxycortisone, wherein the 9a-halogen is of atomic weightbetween seventeen and eighty, inclusive.

2. A compound selected from the group consisting of 1 dehydro 60:,21difluoro 9a halo 2l-desoxyhydrocortisone and 1 dehydro-60:31 difluoro90chalo-21-desoxycortisone, wherein the 9a-halogen is of atomic weightbetween seventeen and eighty, inclusive.

3. 1 dehydro 6a,2l difiuoro 9a halo 2l-desoxyhydrocortisone, wherein the9a-halogen is of atomic weight between seventeen and eighty, inclusive.

4. 1 dehydro 6a,9oc,21 trifiuoro 21 desoxyhydrocortisone.

5. 1 dehydro 60:,21 difluoro 9m chloro 21- desoxyhydrocorfisone.

6. 1 dehydro 60:,21 difluoro 9oz bromo 21- desoxyhydrocortisone.

7. 1 dehydro 604,21 difluoro 9a halo 21-desoxycortisone, wherein the9a-halogen is of atomic weight between seventeen and eighty, inclusive.

8. 1-dehydro-6a,9a,2l-trifluoro-Zl-desoxycortisone.

9. 1 dehydrb 6a,21 difluoro 9a chloro 21- desoxycortisone.

10. 1 dehydro 60;,21 difluoro 9oz bromo 21- desoxycortisone.

References Cited in the file of this patent I UNITED STATES PATENTS2,783,226 Gould et a1. Feb. 26, 1957 2,813,883 Herr -1 Nov. 19, 19572,814,632 Nussbaum Nov. 26, 1957 OTHER REFERENCES Tannhauser et 211.: J.A. C. S. 78, 2658-9 1956). Herz et al.: J. A. C. S. 78, 4812 (1956).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,838,537 June 10, 1958 George B. Spero et a1.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 4, line 62, for atoms read atom; column 5, line 1, for reachedread reaeted; lines 4 and 5, for defluoro read di fluoro-; column 7,line 7 3, for 63- read 6oc; column 10, line 51, for the empiricalformula reading 02313280 3, read -C H O F Signed and sealed this 18thday of November 1958.

[SEAL] Attest: KARL H. AXLINE, ROBERT C. WATSON,

Attestz'ng Ofiioer. Commissz'oner of Patents.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1 - DEHYDRO - 6,21 -DIFLUORO - 9A - HALO - 21 - DESOXYHYDROCORTISONE AND 1 - DEHYDRO -6,21 - DIFLUORO - 9AHALO-21-DESOXYCORTISONE, WHEREIN THE 9A-HALOGEN ISOF ATOMIC WEIGHT BETWEEN SEVENTEEN AND EIGHTY, INCLUSIVE.